The receptor system for Interleukin-6 (IL-6) is composed of two distinct receptor subunits designated gp80 (IL-6R) and gp130 (reviewed in Hirano et al., 1994). These two receptor proteins belong to the cytokine receptor superfamily of Bazan (1990). The 3-dimensional structure of the human Growth Hormone Receptor (hGHR), a member of this family, has been revealed by crystallography (DeVos et al., 1992), from which the residues which interact with the ligand and those which mediate the interaction between the two receptor subunits in their extracellular domains, have been determined. The alignment of part of the amino acid sequence of the extracellular domain of the IL-6R and hGHR sequences based on Bazan's model is shown schematically in FIG. 1.
IL-6 is a pleiotropic cytokine which has a number of important biological activities (see Revel, 1992, for review). Further, IL-6 has been implicated in the growth and progression of human multiple myeloma (Klein et al., 1990).
In fact, IL-6 is a growth factor for B-lymphocyte leukemic cells of Multiple Myeloma. These leukemic cells are also called plasmacytoma or myeloma cells, as they are derived from mature B-lymphocytes or plasma cells. When fused to antibody-producing B-cells, these myeloma or plasmacytoma cells are called hybridoma cells.
In view of the fact that IL-6 is a growth factor for such plasmacytoma or myeloma cells, there has been a long-felt need to obtain specific IL-6 inhibitors which may be used to block the IL-6-mediated or IL-6-dependent growth of such plasmacytoma/myeloma cells, and thereby provide a way for treating Multiple Myeloma, a disease affecting a very large number of people worldwide. To this end, Grube and Cochrane (1994) have described a peptide derived from IL-6R, called peptide 249-264 (i.e. a peptide having the amino acid residues from residue No. 249 to residue No. 264 of the IL-6R amino acid sequence), which is capable of inhibiting the growth of murine plasmacytoma B9 cells. It is also known that IL-6 plays a role in the inhibition of other diseases, such as osteoporosis and autoimmune diseases.
Heretofore, neither the specific peptides of the present invention, nor their specific biological activities and other characteristics such as, for example, their specificity for certain monoclonal antibodies, have been described.
It is therefore an aim of the present invention to provide new peptides derived from IL-6R which are capable of inhibiting the IL-6-dependent growth of human myeloma or murine plasmacytoma cells.
It is another aim of the present invention to provide such new peptides which are further characterized by virtue of their defining linear epitopes within the IL-6R sequence, which are the binding sites of monoclonal antibodies (Mabs) which are themselves capable of blocking IL-6 activity.
Yet another aim of the invention is to provide a chemical synthesis process for the preparation of the new peptides.
A yet further aim of the invention is to provide pharmaceutical compositions containing the new peptides.